This invention is concerned with compounds of structural formula I: ##STR1## wherein X is --CH.dbd.CH--, --CH.sub.2 --CH.sub.2 --, --CH.sub.2 --O--, --O--CH.sub.2 --, --S--CH.sub.2 --, --CH.sub.2 --S--, --S-- or --O--, and R is a 5- or 6-membered nitrogen heterocyclic ring optionally fused to a benzo group, which are antiemetic agents because of their peripheral dopamine antagonist activity.
Severe emesis, and gastro-oesophageal reflux and/or dyspepsia caused by stimulation of peripheral dopamine receptors, are responsive to treatment with dopamine antagonists such as antipsychotic agents. However, such treatment may be accompanied by rather pronounced undesirable central nervous system effects. Furthermore, in the treatment of parkinsonism with a dopaminergic agent, such as bromocriptine or 1-dopa, the severe emetic and other side effects thereof cannot be treated successfully with a centrally active dopamine antagonist without also blocking the desired antiparkinsonian action. Thus, there was a need for a drug which would control side effects of that origin but would not have the undesirable central effects of known dopamine antagonists nor interfere with the central dopamine agonist activity of a dopaminergic agent. One such agent, domperidone, has been described in British Pat. No. 1,542,514.
Now, with the present invention there is provided a group of novel compounds which have been derived from powerful dopamine antagonists in a manner that limits or eliminates their ability to traverse and blood-drain barrier and are thereby peripherally selective dopamine antagonists and are useful for the treatment of emesis caused by stimulation of dopamine receptors of the chemoreceptor trigger zone, as well as emesis and nausea resulting from other causes including post operative emesis, chronic pediatric vomiting, radiotherapy and chemotherapy induced emesis and nausea associated with migraine attacks and dysmenorrhea or arising idiopathically.
They are also useful in the treatment of gastrointestinal disorders, such as gastro-oesophageal reflux caused by stimulation of dopamine receptors in the stomach or other causes and dysepepsia arising from delayed gastric emptying, post prandial dyspepsia or dyspepsia of unknown etiology.
There are also provided novel processes for the preparation of the novel compounds; pharmaceutical formulations employing one of the novel compounds as the active agent alone or in combination with a dopamine agonist; and a method of treating emesis, gastro-oesophageal reflux and/or dyspepsia by the administration of an effective dopamine antagonistic amount of a novel compound of this invention.